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Treatment of induced oligometastatic disease after partial response to systemic antineoplastic therapy in non-small cell lung cancer (NSCLC) remains controversial. The introduction of immune checkpoint inhibitors (ICIs) has revolutionised the treatment of stage IV NSCLC. While ICI combined with chemotherapy (ChT) leads to longer duration of response and higher response rates compared with ChT alone, it can also cause serious adverse events (AEs) resulting in treatment discontinuation. In case of treatment discontinuation due to AEs after partial response to systemic treatment, surgical treatment of residual disease can be considered as it could lead to complete response. We present a case of a patient with stage IV NSCLC who is currently alive without any signs of cancer after partial response to ICI/ChT followed by surgical removal of residual disease.

BackgroundImmune checkpoint inhibitors (ICIs) have become a mainstay of cancer treatment. Their immune-boosting quality has one major drawback, their proclivity to induce a broad array of immune-related adverse events (irAEs) affecting, among others, the liver and sharing some similarities with classic autoimmune liver diseases (AILD).We aimed to compare clinical, laboratory and histological features of patients with liver-related irAEs and AILD.MethodsWe systematically compared liver irAEs with AILD, namely autoimmune hepatitis (AIH) and primary biliary cholangitis, regarding their clinical, laboratory, and histological features.ResultsTwenty-seven patients with liver irAEs (ICI group) and 14 patients with AILD were identified. We observed three distinct ICI-induced histological liver injury patterns: hepatitic (52%), cholangitic (19%), and mixed (29%). When comparing the ICI and AILD groups, centrilobular injury as well as granuloma formation were more prevalent in the former (p=0.067 and 0.002, respectively). CD4+/CD8+ T cell ratios were heterogeneous between the two groups, without statistically significant difference but with a trend toward increased CD8+ T cells among hepatitic irAEs as compared with AIH. Pattern of liver function test alteration was predictive for the type of irAEs but did not correlate with histological severity.ConclusionsLiver irAEs have broad clinical, laboratory and histological presentations. Histological features of irAEs and AILD are distinct, likely underpinning their different immunological mechanisms.

In advanced non-small cell lung cancer (NSCLC), response to immunotherapy is difficult to predict from pre-treatment information. Given the toxicity of immunotherapy and its financial burden on the healthcare system, we set out to identify patients for whom treatment is effective. To this end, we used mutational signatures from DNA mutations in pre-treatment tissue. Single base substitutions, doublet base substitutions, indels, and copy number alteration signatures were analysed in $$m=101$$ m = 101 patients (the discovery set). We found that tobacco smoking signature (SBS4) and thiopurine chemotherapy exposure-associated signature (SBS87) were linked to durable benefit. Combining both signatures in a machine learning model separated patients with a progression-free survival hazard ratio of 0.40$$_{-0.17}^{+0.28}$$ - 0.17 + 0.28 on the cross-validated discovery set and 0.24$$_{-0.14}^{+0.31}$$ - 0.14 + 0.31 on an independent external validation set ($$m=56$$ m = 56 ). This paper demonstrates that the fingerprints of mutagenesis, codified through mutational signatures, select advanced NSCLC patients who may benefit from immunotherapy, thus potentially reducing unnecessary patient burden.

Helicobacter pylori infects the gastric mucosa of a large number of humans. Although asymptomatic in the vast majority of cases, H pylori infection can lead to the development of peptic ulcers gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Using a variety of mechanisms, H pylori locally suppresses the function of the host immune system to establish chronic infection. Systemic immunomodulation has been observed in both clinical and pre-clinical studies, which have demonstrated that H pylori infection is associated with reduced incidence of inflammatory diseases, such as asthma and Crohn's disease. The introduction of immunotherapies in the arsenal of anti-cancer drugs has revealed a new facet of H pylori-induced immune suppression. In this review, we will describe the intimate interactions between H pylori and its host, and formulate hypothtyeses describing the detrimental impact of H pylori infection on the efficacy of cancer immunotherapies.

Objectives: Older patients with metastatic renal cell carcinoma (mRCC) were underrepresented in pivotal trials. Materials and methods: Consecutive patients with mRCC treated at Aarhus University Hospital with first line tyrosine kinase inhibitors (TKI), mTOR inhibitors, or checkpoint immunotherapy (CPI) were retrospectively analyzed in age-subgroups; ≥ 75, 65–74, and < 65 years, with overall survival (OS), time-to-treatment discontinuation (TTD), and progression-free survival (PFS) as endpoints. Hazards ratios were adjusted (aHR) for International Metastatic RCC Database Consortium (IMDC) risk factors, histology, and age. Results: Of 838 patients, 159 (19%) were ≥ 75 years, 324 (39%) 65–74 years, and 355 (42%) < 65 years. Treatments were TKI in 729 (87%) patients, mTOR in 43 (5%) and CPI in 67 (8%). Older patients ≥ 75 years compared with 65–74 years and < 65 years had lower toxicity-adjusted median doses of pazopanib, 300 mg vs. 400 mg vs. 600 mg, respectively, (p < 0.001), and sunitinib, 25 mg vs. 37.5 mg vs. 50 mg, respectively (p < 0.001); numerically fewer doses of CPI, median 2 vs. 5 vs. 5, respectively, (p = 0.2); a higher proportion had dose reduction/interruption, 76% vs. 55% vs. 41%, respectively, (p < 0.001); and shorter mean time to dose reduction/interruption, 0.5 months vs. 1.9 months vs. 3.4 months, respectively, (p < 0.001). After adjusting IMDC prognostic factors and histology in multivariate analyses, age did not impact OS (aHR 1.0; 95% CI 0.99–1.02, p = 0.2), TTD (aHR 1.0; 95% CI 0.99–1.01, p = 0.4) or PFS (aHR 1.0, 95% CI 0.99–1.01; p = 0.9). Conclusion: Older patients with mRCC were more prone to toxicity; but age did not impact outcomes. Proactive dose modification/interruption and awareness may help to reduce toxicity while maintaining efficacy.

Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, by reshaping the prognosis of many cancers and are progressively becoming the standard of care. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), of which cardiovascular irAEs are particularly feared. ICI-induced myocarditis is often a diagnostic challenge because of the vast heterogeneity of clinical presentations, and it is associated with a high mortality rate of around 50%. The present article summarizes the cardiac manifestations, the diagnostic strategy and the therapeutic management of patients with ICI-induced myocarditis used in the treatment of cancer.

Side effects of immune checkpoint blockade are often said to be infrequent and usually mild. The uniqueness of endocrine immune-related adverse events is their non-reversibility, with incidence and prevalence destined to increase in the coming years, particularly if immunotherapy is used at earlier stages of neoplastic disease. Immune-related hypophysitis is one of these observed endocrine adverse events. It is often difficult to diagnose, sometimes occurring without specific symptoms. It can lead to irreversibly altered functioning of diverse endocrine glands. Radiographically, the differential diagnosis of hypophysitis includes pituitary apoplexy and primary and secondary neoplastic lesions. Immune-related hypophysitis is most common with single-agent anti-CTLA-4, followed by the combination of anti-CTLA-4 and anti-PD-1, while occurs infrequently when anti-PD-1 or anti-PD-L1 agents are administered alone. Hypophysitis with immune checkpoint blockade requires early recognition, diagnosis, and treatment. Patients can present with headache, visual disturbances or other endocrine-related syndromes or they can be asymptomatic. The manifestation of symptoms should prompt blood analysis and magnetic resonance imaging of the brain. Imaging is important to exclude secondary meningeal or parenchymal lesions. Management should include discontinuation of the immune checkpoint blockade, initiation of corticosteroid therapy and eventually hormone replacement therapy. Hypophysitis impacts treatment of the disease and usually requires long-term management of this irreversible side effect. A multidisciplinary team approach is merited to insure the correct diagnosis and management of immune-related hypophysitis.

Resume Les indications des inhibiteurs de checkpoint (ICP) immunitaire sont maintenant tres etendues et ont fait emerger des complications endocriniennes specifiques avec lesquelles les oncologues ont du se familiariser. L’hypophysite en est un exemple typique, devenue une complication non rare des ICPs, touchant jusqu’a 10 % des patients traites par anti-CTLA4. Elle survient classiquement deux a trois mois apres l’initiation du traitement. Le tableau associe typiquement cephalees et alteration de l’etat general, associees a une hyponatremie. Les atteintes hormonales les plus frequentes touchent les secteurs thyreotropes, gonadotrope et corticotrope. L’atteinte corticotrope fait la gravite de cette pathologie, necessitant la mise en place urgente d’une supplementation, sans attendre la confirmation biologique dans les cas severes. L’IRM doit etre systematiquement realisee, essentiellement pour eliminer les diagnostics differentiels, dont les metastases hypophysaires. L’hypophysite induite par les ICPs de type anti-PD1/PDL1 est une entite a part, de survenue retardee, pauci-symptomatique, mais caracterisee par une insuffisance corticotrope systematique et definitive, le plus souvent isolee au vu des premieres donnees publiees. Le traitement repose sur la corticotherapie a forte dose uniquement en cas de cephalees resistantes ou d’insuffisance corticotrope decompensee, et sur la supplementation hormonale systematique des deficits antehypophysaires. Les patients necessiteront une supplementation hormonale a vie, et doivent etre pris en charge et eduques en endocrinologie. Une fois l’episode aigu resolu, l’immunotherapie peut etre poursuivie si le patient en a un benefice. Compte tenu du caractere peu symptomatique et de la gravite potentielle de ces hypophysites, une surveillance biologique systematique est necessaire pendant le traitement par ICPs.

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.

Background Immune checkpoint inhibitors are associated with unique immune-related adverse events (irAEs). As most of the immune checkpoint inhibitors are new to the market, it is important to conduct studies using real-world data sources to investigate their safety profiles. Objective The aim of the study was to develop a framework for signal detection and filtration of novel irAEs for 6 Food and Drug Administration–approved immune checkpoint inhibitors. Methods In our framework, we first used the Food and Drug Administration’s Adverse Event Reporting System (FAERS) standardized in an Observational Health Data Sciences and Informatics (OHDSI) common data model (CDM) to collect immune checkpoint inhibitor-related event data and conducted irAE signal detection. OHDSI CDM is a standard-driven data model that focuses on transforming different databases into a common format and standardizing medical terms to a common representation. We then filtered those already known irAEs from drug labels and literature by using a customized text-mining pipeline based on clinical text analysis and knowledge extraction system with Medical Dictionary for Regulatory Activities (MedDRA) as a dictionary. Finally, we classified the irAE detection results into three different categories to discover potentially new irAE signals. Results By our text-mining pipeline, 490 irAE terms were identified from drug labels, and 918 terms were identified from the literature. In addition, of the 94 positive signals detected using CDM-based FAERS, 53 signals (56%) were labeled signals, 10 (11%) were unlabeled published signals, and 31 (33%) were potentially new signals. Conclusions We demonstrated that our approach is effective for irAE signal detection and filtration. Moreover, our CDM-based framework could facilitate adverse drug events detection and filtration toward the goal of next-generation pharmacovigilance that seamlessly integrates electronic health record data for improved signal detection.

Immune checkpoint inhibitors are reshaping the prognosis of many cancer and are progressively becoming the standard of care in the treatment of many tumour types. Immunotherapy is bringing new hope to patients, but also a whole new spectrum of toxicities for healthcare practitioners to manage. Oncologists and specialists involved in the pluridisciplinary management of patients with cancer are increasingly confronted with the therapeutic challenge of treating patients with severe and refractory immune-related adverse events. In this Personal View, we summarise the therapeutic strategies that have been used to manage such toxicities resulting from immune checkpoint inhibitor treatment. On the basis of current knowledge about their pathogenesis, we discuss the use of new biological and non-biological immunosuppressive drugs to treat severe and steroid refractory immune-related adverse events. Depending on the immune infiltrate type that is predominant, we propose a treatment algorithm for personalised management that goes beyond typical corticosteroid use. We propose a so-called shut-off strategy that aims at inhibiting key inflammatory components involved in the pathophysiological processes of immune-related adverse events, and limits potential adverse effects of drug immunosuppression on tumour response. This approach develops on current guidelines and challenges the step-by-step increase approach to drug immunosuppression.

AIMS: Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors restore antitumor immunity, but many autoimmune side-effects have been described. Diabetes mellitus is a rare complication, and little data concerning its pathophysiology and phenotype have been published. This study aimed to describe both pancreatic endocrine and exocrine functions, immunological features and change in pancreas volume in subjects with diabetes mellitus induced by PD-1 and PD-L1 inhibitors. METHODS: We analyzed the data of six subjects treated with immunotherapy who presented acute diabetes. RESULTS: There were five men and one woman. Median age was 67 years (range 55-83). Three subjects were treated with nivolumab, two with pembrolizumab and one with durvalumab. Median time to diabetes onset after immunotherapy initiation was 4 months (range 2-13). Four patients presented fulminant diabetes (FD); none of these had type 1 diabetes (T1D)-related autoantibodies, none of them had T1D or FD-very high-risk HLA class II profiles. The bi-hormonal endocrine and exocrine pancreatic failure previously reported for one FD patient was not found in other FD subjects, but glucagon response was blunted in another FD patient. Pancreas volume was decreased at diabetes onset in 2 FD patients, and all patients presented a subsequent decrease of pancreas volume during follow-up. CONCLUSIONS: In the patients presented herein, immunotherapy-induced diabetes was not associated with T1D-related autoantibodies. The hormonal and morphological analysis of the pancreatic glands of these six cases contributes to the understanding of the underlying and probably heterogeneous mechanisms. There is a need to find biomarkers to identify patients at risk to develop these new forms of diabetes at early stages of the process to prevent ketoacidosis and to evaluate preventive strategies.

Within the last few years we have treated still more types of cancer with immune checkpoint inhibitors - anti-cytotoxic T-lymphocyte-associated-4 antibodies and anti-program-med cell death 1/anti-programmed cell death ligand 1 antibodies. A unique set of side effects called immune related adverse events irAEs may occur during treatment. Although severe irAEs remain rare they can become life-threatening. Early detection of irAEs and initiation of relevant treatment are therefore crucial to reduce the risk of long-term seque-lae. We provide a detailed overview of irAEs and recommendations for treatment according to established guidelines. Within the last few years we have treated still more types of cancer with immune checkpoint inhibitors - anti-cytotoxic T-lymphocyte-associated-4 antibodies and anti-program-med cell death 1/anti-programmed cell death ligand 1 antibodies. A unique set of side effects called immune related adverse events irAEs may occur during treatment. Although severe irAEs remain rare they can become life-threatening. Early detection of irAEs and initiation of relevant treatment are therefore crucial to reduce the risk of long-term seque-lae. We provide a detailed overview of irAEs and recommendations for treatment according to established guidelines.

Hodgkin lymphoma (HL) was one of the first few cancers to be cured first with radiotherapy alone and then with a combination of chemotherapy and radiotherapy. Around 80% of the patients with HL will be cured by first-line therapy. However, the ionising radiation not only produces cytotoxicity but also induces alterations in the microenvironment, and patients often struggle with the long-term consequences of these treatments, such as cardiovascular disorders, lung diseases and secondary malignancies. Hence, it is essential to improve treatments while avoiding delayed side-effects. Immunotherapy is a promising new treatment option for Hodgkin lymphoma, and anti- programmed death-1 (PD1) agents have produced striking results in patients with relapsed or refractory disease. The microenvironment of Hodgkin lymphoma appears to be unique in the field of human disease: the malignant Reed-Sternberg cells only constitute 1% of the cells in the lymphoma, but they are surrounded by an extensive immune infiltrate. Reed-Sternberg cells exhibit 9p24.1/PD-L1/PD-L2 copy number alterations and genetic rearrangements associated with programmed cell death ligand 1/ ligand 2 (PD-L1/2) overexpression, together with major histocompatibility complex-I (MHC-I) and major histocompatibility complex-II (MHC-II) downregulation (which may facilitate the tumour's immune evasion). Although HL may be a situation in which defective immune surveillance is restored by anti-PD1 therapy, it challenges our current explanation of how anti-PD1 agents work because MHC-I expression is required for CD8-T-cell-mediated tumour antigen recognition. Here, we review recent attempts to understand the defects in immune recognition in HL and to design an optimal evidence-based treatment for combination with anti-PD1.

INTRODUCTION: Life expectancy evaluation is crucial when selecting patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on three objective variables (number of metastatic sites, lactate dehydrogenase (LDH) and serum albumin) was validated in patients treated with cytotoxics and targeted therapies. We aimed to determine if those factors were applicable to immune-checkpoint therapies (ICTs) in phase I trials and to evaluate new variables that may preclude a better prognosis in patients receiving ICT. PATIENTS AND METHODS: We conducted a retrospective analysis of survival risk factors in a discovery cohort of 155 patients enrolled into ICT phase I trials at our institution. We computed univariate analysis and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in phase I ICT trials was used to prospectively validate this score. RESULTS: A total of 155 patients (M/F: 83/72; median age 59) receiving an experimental ICT between March 2012 and January 2016 were included in the discovery cohort. An MVA assessing the RMH score variables showed that low albumin (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.05-2.86) and LDH > upper limit normal (ULN) (HR 1.88, 95% CI 1.12-3.15) were independent negative prognostic factors for OS. Interestingly, neutrophil-to-lymphocyte ratio (NLR) > 6 (HR 1.75, 95% CI 1.04-2.95) was associated with a decrease in OS. The number of metastases was not associated with a poorer outcome for this ICT cohort (HR 0.83, 95% CI 0.51-1.35). A risk score based on the results of the MVA (NLR > 6 = 1; LDH > ULN = 1; albumin < 35 g/l = 1) showed that patients presenting a high score (>1) had a significantly shorter OS (20.4 weeks; 95% CI 5.7-35.2) compared to those with a low score (0 or 1) (68.9 weeks; 95% CI 50-83.7) (HR 2.9, 95% CI 1.87-4.64). In the validation cohort of 113 patients, again the patients presenting a high score showed an inferior OS (HR 6.3, 95% CI 2.7-14.8). CONCLUSION: In ICT phase I trials, traditional prognostic variables included in the RMH score may be suboptimal to determine patient's prognosis. In this context, the NLR is a significant prognostic variable. The Gustave Roussy Immune Score, based on albumin, LDH and NLR, allows a better selection of patients for ICT phase I trials.

For decades, immunotherapy strategies have failed to succeed in lung cancer. However, the recent success of immune checkpoint inhibitors and the progress in the understanding of the immunobiology of lung cancer have changed this paradigm. Here we review ongoing clinical trials and recent results obtained with these novel lung cancer immunotherapies.

Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade -based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials. Accumulating preclinical evidence supports their clinical development. However, conflicting results and controversies between in vitro and in vivo data point to the need for comprehensive ancillary studies to be performed in upcoming clinical trials to better understand the mechanism of action of anti-OX40 mAbs-based therapy.

Treatment with checkpoint inhibitors has revolutionised the treatment of many different cancers with a significant improvement in cancer survival. However, a different type of adverse effects is seen compared to standard chemotherapy called immune-related adverse effects (irAE). In this review, we give recommendations on how to diagnose and treat the most common and severe neurologic irAE. We advise clinicians to be cautious to classify neurologic irAE as well-known nosologic entities, since their presentation, cause and treatment often is different.